A National Cancer Clinical Trials System for the 21st Century Reinvigorating the NCI Cooperative Group Program (2010) / Chapter Skim
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1 Introduction
1 Introduction
Pages 41-76
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From page 41... ...
However, the ability to translate biomedical discoveries into advances in cancer care remains dependent on the clinical trials system. Clinical trials provide an essential link between scientific discovery and clinical practice.
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Numerous stakeholders conduct clinical trials with various goals across the spectrum of research. While industry trials primarily focus on drug discovery and development activities with the potential for a substantial return on investment, publicly sponsored trials have a more diverse portfolio, from small, proof-of-concept Phase I and II studies that typically enroll patients with metastatic disease who have already had one or more lines of therapy to large Phase III studies that may focus on adjuvant or neoadjuvant therapy, first-line therapy for metastatic disease, or prevention strategies.
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Within the portfolio of NCI-supported clinical trials, the Cooperative Group Program primarily focuses on late-stage translation activities, such as large Phase II and Phase III clinical trials that may have implications for changing treatment practices directly relevant to patient care. Individual institutions can rarely undertake such trials because it would take too long to accrue a sufficient number of patients to achieve timely results.
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was established to ensure that community physicians and cancer patients not treated in academic medical centers had access to cancer clinical trials and to boost the rates of accrual to clinical trial protocols. NCI established the Minority-Based CCOP in 1990 to increase the involvement of racial and ethnic minority patients in clinical trials research and to improve access to the latest advances in cancer treatment, prevention, and control (NCI, 2003)
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From page 45... ...
Cooperative Group research has led to the • development of new standards for the management of patients with cancer; • development of sophisticated investigative techniques; • collection of data to obtain regulatory approval for new drugs or new drug indications; • refinement in diagnosis and treatment of cancer based on the iden tification of histologic subtypes of tumors and the recognition of prognostic variables; • development of adjuvant and neoadjuvant chemotherapy and con current chemoradiotherapy for solid tumors through studies that combine modalities; • refinement of the use of chemotherapy through the study of new agents and different dosing schedules; • comparison of new cancer treatments against the best available treatments; and • development of novel therapeutic agents in Phase I and II trials (Mauer et al., 2007)
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A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX 1-2 A Sampling of Cooperative Group Accomplishments Pediatric cancers • evelopment of effective treatments for childhood cancers, including Wilms' D tumor, leukemia, and rhabdomyosarcoma, which have improved the cure rates for childhood cancers from less than 10 percent when the Cooperative Groups were first founded to nearly 80 percent today. The outcome of acute lympho blastic leukemia (ALL) has progressed from a 6-month median survival to an 80 percent overall cure rate. There has also been substantial improvement in the 5-year cancer survival rates; between 1960 and 2000, the 5-year rate of survival for children with solid tumors increased from 27 to 80 percent. • he high rate of participation of children in Cooperative Group trials; if a clinical T trial is available, 50 to 60 percent of children eligible are enrolled and 90 per cent of children under age 5 years are enrolled. With high participation rates, the results of clinical trials performed by COG define the standard of care for children with cancer in the United States and elsewhere.
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From page 47... ...
. Breast cancer • andmark trials supporting the use of more conservative, less disfiguring treat L ment of breast cancer, altering the standard of care toward breast-conserving therapy. These trials demonstrated equivalent survival between patients under going radical mastectomy and patients undergoing total mastectomy and then equivalent rates of survival and in-breast recurrence between patients under going lumpectomy and patients undergoing total mastectomy when lumpec tomy and mastectomy were followed by radiation therapy (NSABP)
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(ACRIN) . Lung cancer • evelopment of combined-modality treatment for Stage III non-small-cell lung D cancer (NSCLC)
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INTRODUCTION • emonstration that the 3-year disease-free survival rate is a valid surrogate D of the 5-year overall survival rate in patients receiving adjuvant 5-FU-based chemotherapy for resected colon cancer (NCCTG)
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. Childhood Cancer One of the major accomplishments in research on and the treatment of pediatric cancer is the high rate of participation of children in Cooperative Group clinical trials.
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For example, landmark trials from NSABP first demonstrated equivalent rates of survival between patients undergoing a radical mastectomy and patients undergoing a total mastectomy and then between patients undergoing a
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Copyright 2009 by Children's Oncology Group. mastectomy and patients undergoing a lumpectomy followed by radiation therapy, ushering in an era of breast-conserving therapy (Fisher et al., 1977, 1985, 2002a,b)
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. For example, CALGB defined the role of adjuvant paclitaxel as part of adjuvant therapy for breast cancer, leading to FDA approval of the use of paclitaxel for this indication (Green et al., 2008; Henderson et al., 2003)
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Examples include trials that are evaluating colorectal cancer screening using computed tomography (CT) colonography, breast cancer screening using ultrasound and magnetic resonance imaging, and lung cancer screening using CT.
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Publicly funded clinical trials also play a vital, complementary role in advancing science and patient care, particularly by addressing questions that are important to patients but are less likely to be top priorities of industry. With many new therapies already in clinical use, and more than 800 cancer therapeutics in development (PhRMA, 2009)
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Clinical trials evaluating therapies in rare diseases may not be top priorities for industry, since the research and development costs may not be recouped by the small number of patients who receive the therapy. Likewise, trials that assess multimodality therapies, such as radiation therapy, surgery, or devices in combinations with drugs provide data that inform clinical practice, but are usually not high priorities of industry.
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The Cooperative Group Program provides a unique environment for investigators to conduct clinical trials. The public and academic nature of the Groups enables the pooling of public resources to conduct studies in the public interest.
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Radiotherapy with Concomitant and Adjuvant Temozolomide for Patients with 1p/19q Codeleted Anaplastic Glioma RTOG-0525 Trial Comparing Conventional Adjuvant Temozolomide with Dose-Intensive Temozolomide in Patients with Newly Diagnosed Glioblastoma Breast Cancer ACOSOG-Z1031 Randomized Trial Comparing 16 to 18 Weeks of Neoadjuvant Exemestane (25 mg daily) , Letrozole (2.5 mg)
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The duration question regarding Phase III adjuvant chemotherapy has clear public health implications and is part of the International Duration Evaluation of Adjuvant Chemotherapy meta-analysis, which leverages other international trials with compatible endpoints. Study in a very rare subset of a rare disease, in a clinical setting using Phase III a specific therapeutic approach (trimodality therapy)
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of the Uterus RTOG-0724 Randomized Study of Concurrent Chemotherapy and Pelvic Radiation Therapy with or without Adjuvant Chemotherapy in High-Risk Patients with Early-Stage Cervical Carcinoma Following Radical Hysterectomy GOG-0238 Randomized Trial of Pelvic Irradiation with or without Concurrent Weekly Cisplatin in Patients with Pelvic-Only Recurrence of Carcinoma of the Uterine Corpus GOG-0248 Randomized Trial of Temsirolimus (NCI-Supplied Agent, NSC #683864, IND #61010) or the Combination of Hormonal Therapy Plus Temsirolimus in Women with Advanced, Persistent, or Recurrent Endometrial Carcinoma
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Phase III Evaluating chemoradiation with or without adjuvant chemotherapy in Phase III women with high-risk early-stage cervical cancer after hysterectomy with involving standard agents. A study of radiation therapy vs.
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, Lenalidomide and Low Dose Dexamethasone for Induction, in Patients with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant S0816 Trial of Response-Adapted Therapy of Stage III-IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Imaging Lung Cancers CALGB-30506 Randomized Trial of Adjuvant Therapy in Early-Stage Non-Small Cell Lung Cancer Evaluating the Potential Utility of a Genomic Prognostic Model to Identify Patients as Candidates for Adjuvant Chemotherapy S0819 Randomized Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer E1508 Randomized Study of Cisplatin and Etoposide in Combination with Either Hedgehog Inhibitor GDC-0449 or IGF-1R MOAB IMC-A12 for Patients with Extensive Stage Small Cell Lung Cancer Pediatric Cancers AALL0232 High-Risk B-Precursor Acute Lymphoblastic Leukemia AALL0331 Standard-Risk B-Precursor Acute Lymphoblastic Leukemia AALL0434 Intensified Methotrexate, Nelarabine (Compound 506U78; IND# 52611)
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Evaluating the benefit of augmented intensity consolidation as a Phase III therapeutic approach. Involves multiple research questions in a 2 × 2 randomization design Phase III evaluating nelarabine therapy and interim maintenance therapy with Capizzi methotrexate or high-dose methotrexate.
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Problems with the current cancer clinical trials system are readily acknowledged by a number of stakeholders: clinical investigators, patient 3 CCOP enables community physicians to participate in and enroll patients in Cooperative Group Program clinical trials. See http://prevention.cancer.gov/programs-resources/programs/ccop.
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Current NCI activities include the implementation of several recommendations from the Clinical Trials Working Group and Translational Research Working Group reports that have the potential to address some of the recognized challenges. Clinical Trial Costs Outstrip Program Funding In recent years, NCI funding for the Cooperative Group Program has been flat and has been declining when the funding is adjusted for inflation.
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. Inadequate Patient and Physician Involvement in Cancer Clinical Trials Few patients and physicians participate in clinical trials for adult cancers.
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The first workshop, Improving the Quality of Cancer Clinical Trials, held on October 4 and 5, 2007, focused on the science underpinning clinical trials; collaborations among Cooperative Groups, industry, and academia; and the regulatory issues affecting clinical trial development, especially the early stages of development. The second workshop, MultiCenter Phase III Clinical Trials and NCI Cooperative Groups, held on July 1 and 2, 2008, explored the organization and operations of the Cooperative Group Program, patient and physician involvement in Cooperative Group research, and data collection requirements, as well as clinical trial cost and reimbursement issues.
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A NATIONAL CANCER CLINICAL TRIALS SySTEM American Cancer Society, the American Society of Clinical Oncology, the Association of American Cancer Institutes, and C-Change. COMMITTEE APPOINTMENT AND CHARGE The NCI asked the IOM to examine a broad a number of topics relevant to cancer clinical trials and the organization and operation of the Cooperative Group Program and to make recommendations that could improve the quality of cancer clinical trials conducted through the program (Box 1-3)
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The collective environment in which clinical trials are conducted influences the pace of clinical advances. The committee then described the needs of an ideal cancer clinical trials system of the near future, circa 2015 (see Box 1-4)
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Chapter 3 provides an overview of the structure, organization, and funding of cancer clinical trials and the Cooperative Group Program. It also delineates the inefficiencies in the current system and discusses the collaborative nature of cancer clinical trials.
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2005. Clinical trials trickling away.
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2006. Enhancing Cancer Treatment Through Improved Understanding of the Critical Components, Economics and Barriers of Cancer Clinical Trials.
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2002a. Twenty-year follow-up of a randomized trial comparing total mastec tomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.
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2009. Multi-Center Phase III Clinical Trials and NCI Cooperative Groups: Workshop Summary.
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2006. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group.
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2002. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: Initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study.
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